Successful vaccine delivery requires knowledge of the signals that direct reactive lymphocytes to potential sites of infection. For systemic pathogens, intramuscular or subcutaneous routes of immunization have proven efficacious in inducing protective immune responses. For mucosal pathogens such as HIV, gonococci, and Chlamydia, use of these same routes failed to induce a mucosal antibody response. However, immunization via the intestinal mucosa induced secretory antibody responses at all mucosal surfaces, leading to definition of a common mucosal immune system (CMIS) that is functionally separate from the systemic immune system. It was later shown that lymphocytes homing to the intestinal mucosa expressed a4b7 integrin receptors specific for the MAdCAM addressin which was selectively expressed on intestinal blood vessels, while lymphocytes homing to systemic tissues expressed the a4b1 receptor that binds to the systemic vascular ligand, VCAM. These data further distinguished mucosal from systemic homing pathways and led to widespread use of a mucosal immunization scheme to induce protection against mucosal pathogens. The molecular signals directing lymphocytes to nonintestinal mucosae of the eye, lung, and genital tract had not been investigated but were assumed to reflect this intestinal homing pathway. The purpose of our investigations was to define lymphocyte homing pathways to these nonintestinal mucosae to provide a more rational basis for the delivery of vaccines against all mucosal pathogens, and to determine whether the pathways defined for antibody-producing B lymphocytes applied equally to T lymphocytes. In studies initiated last year, we determined that a4b1 was the predominant integrin on T lymphocytes migrating to Chlamydia-infected genital mucosae while VCAM was the dominant vascular addressin, defining a systemic type homing pathway for T cells at this site. We have since extended these studies to Chlamydia-infected pulmonary and conjunctival mucosae and found similar profiles at all nonintestinal sites, indicating that T cells infiltrating mucosae outside of the gastrointestinal tract share homing signals with systemic tissues and not with the intestinal mucosa. In contrast, B lymphocytes infiltrating all mucosal sites, intestinal and nonintestinal, express the a4b7 integrin receptor which allows binding to either MAdCAM or VCAM expressing blood vessels. Therefore, it appears that the CMIS defined for B lymphocytes may not apply equally to T lymphocytes and that systemic immunization may trigger T cells capable of migrating to mucosal sites of infection, with the exception of the intestinal mucosa which possesses a unique profile of homing markers that separates this tissue from all others. This is not surprising given the microbe-rich microenvironment of the intestine and the need to down-regulate T cell reactivity and thus prevent the induction of chronic inflammatory responses to commensal bacteria. Presumably, these evolutionary pressures resulted in a trafficking scheme that distinguished the intestine from other mucosal tissues